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Description of key information

Key value for chemical safety assessment

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COPPER IODIDE

Copper iodide will dissociate following exposure via the inhalation, oral or dermal routes, giving rise to cuprous copper ions (Cu+) and iodide ions (I-) that will be more bioavailable than the parent compound. These species will be independently responsible for any effects seen in the event that organisms are exposed to copper iodide as a result of its production and/or use.

Comparative bioavailability, solubility and toxicity studies have shown that relatively insoluble copper and sparingly soluble copper oxide are less bioavailable than the more soluble copper salts, e.g. copper sulphate pentahydrate and cuprous oxide. The same will be true of less soluble copper iodide. Therefore, in order to fully utilise existing data and avoid unnecessary animal testing, all long-term studies read across from the copper CSR were conducted on soluble copper salts.

Iodine ingested in the form of water soluble salts (such as potassium or sodium iodide) typically result in 100% absorption from the gastro-intestinal tract. Molecular iodine is converted into iodide in the gastro-intestinal tract and thus, information read across from the iodine CSR on the toxicokinetics of iodine and iodide salts is considered equivalent. As for copper, this approach maximises the use of existing data and minimises animal testing.

Use of available data in this way is considered to represent a worst-case scenario for risk assessment purposes.

Summary information on the toxicokinetics of copper and iodine is presented below.

COPPER:

See Chemical Safety report.

IODINE:

Short description of key information:

Molecular iodine and also inorganic compounds of iodine are readily absorbed via the oral and inhalation routes of exposure. In human studies, dermal absorption is not considered to be a significant route of exposure, and represents 1% of the applied dose. Iodine is excreted via urine, faeces, sweat and breast milk.

Discussion:

Absorption:

Iodine (I2) is considered to be readily absorbed through the lungs and the gastrointestinal tract, based on available reports. Radioiodine (as I2vapour) was inhaled in a human volunteer study, where virtually all of the inhaled iodine was removed from the respiratory tract with a half-time of approximately 10 minutes. Much of the clearance of iodine from the respiratory tract was transferred to the gastrointestinal tract which suggested that the initial deposition was primarily in the conducting airways and moved by mucociliary clearance. The rapid absorption of iodine vapour is supported by animal studies in mice, rats, dogs, and sheep.

Iodine that is ingested orally in the form of water soluble salts (such as potassium or sodium iodide) typically results in 100% absorption from the gastro-intestinal tract. Molecular iodine is converted into iodide in the gastro-intestinal tract and thus, information on the toxicokinetics from iodine and iodide salts is considered equivalent.

The dermal absorption of iodine was investigated in humans that received topical applications of131I as potassium iodide or molecular iodine. Results indicated that the dermal absorption of iodine is assumed to be 1%.

Distribution:

Irrespective of the route of exposure to inorganic iodine, the distribution of absorbed iodine is similar. This conclusion is supported by a study in which human subjects were orally exposed to tracer levels of radio-labelled iodine as sodium iodide. The results determined that approximately 20–30% iodine was distributed to the thyroid, and 30–60% was excreted in the urine after approximately 10 hours. Essentially the same results were observed after the ingestion of a tracer dose of Na132I. Similar results were found in human volunteers that inhaled tracer levels of radioiodine as I2. Also, similar results were found in studies in monkeys ingesting iodide and monkeys that inhaled particulate aerosols of sodium iodide.

The human body contains approximately 10–15 mg of iodine. As a proportion of this amount, approximately 70–90% is in the thyroid gland, which accumulates iodine in producing thyroid hormones for export to the blood and other. Under normal circumstances, the concentration of iodine in serum is approximately 50–100 μg/L. Approximately 5% of the iodine is in inorganic form, with the remaining 95% consisting of the various organic forms of iodine, primarily as protein complexes of the thyroid hormones T4 (tetraiodothyronine) and T3 (triiodothyronine). The tissue distribution of iodide and organic iodine are very different and are interrelated by metabolic pathways that lead to the iodination and deiodination of proteins and thyroid hormones in the body. Iodine is predominantly confined to the extracellular fluid. However, tissues that have specialised transport mechanisms for accumulating iodide are exceptions. These tissues include the thyroid, choroid plexus, mammary glands, salivary glands, gastric mucosa, placenta, and sweat glands.

Iodide is actively transported into the thyroid follicle by the Sodium Iodine Symporter (NIS) and is then oxidised to molecular iodine. Following that, iodine is bound to the amino acid tyrosine in thyroglobulin in the colloid to produce the thyroid hormones T3 and T4 and their various intermediates and degradation products. The uptake of iodide into the thyroid depends upon the intake of iodide into the body, with the percentage of thyroid intake increasing with decreasing levels of iodide intake. The uptake of iodide by the foetus increases with the development of the foetal thyroid, and reaches its peak at approximately 6 months of gestation.

Metabolism:

The metabolism of absorbed iodine is expected to be similar, irrespective of the route of exposure to inorganic iodine. Molecular iodine (and ingested sodium iodide and inhaled methyl iodide) all undergo rapid conversion to iodide. For by-products of metabolic reactions in the gastrointestinal tract it has been suggested that these may differ for iodine and iodide, and could be responsible for differences in some reported effects.

Iodine in the thyroid gland is incorporated into the protein, thyroglobulin. Iodine forms covalent complexes with tyrosine residues. The iodination of thyroglobulin is catalysed by the enzyme thyroid peroxidise. Iodination occurs at the follicular cell-lumen interface and the processes involved are the oxidation of iodide to form a reactive intermediate, the formation of monoiodotyrosine and diiodotyrosine residues in thyroglobulin, and the coupling of the iodinated tyrosine residues to form T4 (coupling of two diiodotyrosine residues) or T3 (coupling of a monoiodotyrosine and diiodotyrosine residue) in thyroglobulin. In the thyroid, the T4/T3 ratio is approximately 15:1; however, the relative amounts of T4 and T3 produced can depend on the availability of iodide, as low levels of iodide result in a lower T4/T3 synthesis ratio. The lipophilic T3 and T4 enter the blood via diffusion through the plasma membrane to the blood. More than 99% of both T3 and T4 combine with blood transport proteins, predominantly thyroxine binding globulin. The process is regulated by the pituitary hormone, thyroid stimulating hormone (TSH). TSH is released in response to thyrotropin releasing hormone from the hypothalamus as a response to low blood thyroid hormone level or lowered metabolic rate or body temperature.

The main metabolic pathways for iodine outside the thyroid gland involve the catabolism of T3 and T4 and include:

- Deiodination reactions;

- Ether bond cleavage of thyronine;

- Oxidative deamination and decarboxylation of the side-chain of thyronine; and

- Conjugation of the phenolic hydroxyl group on thyronine with glucuronic acid and sulphate.

Excretion:

The main route of excretion for iodine is via the urine in the iodide form. With respect to the elimination of absorbed iodine, urinary excretion accounts for >97% and faeces accounts for another 1-2%. However, not all iodide that is filtered by the kidney remains in the urine. During steady-state conditions of radioiodine concentration, the renal plasma clearance was about 30% of the glomerular filtration rate. This suggests tubular reabsorption of the element. In other studies investigating the renal clearance in dogs, further evidence for tubular reabsorption of iodide was demonstrated. The exact mechanism for reabsorption has not been clearly established.

Glucuronide and sulphate conjugates of T3, T4 and their metabolites are secreted into the bile. The total biliary secretion of T4 and metabolites was approximately 10-15% of the daily metabolic clearance of T4. In rats, about 30% of T4 clearance has been attributed for by the biliary secretion of the glucuronide conjugate and 5% as the sulphate conjugate. Once the conjugates are secreted, extensive hydrolysis occurs, with the reabsorption of iodothyronine in the small intestine.

Other routes of excretion for absorbed iodine can be through breast milk, saliva, sweat, tears and exhaled air.

The whole body elimination half-time of absorbed iodine has been estimated to be approximately 31 days in healthy adult males. However, considerable inter-individual variability is documented.